Thursday, February 23, 2006

Vancomycin: can we teach the mainstay of therapy for gram-positives new tricks?

Infectious Disease News

February 2006

Future studies will examine the role of vancomycin therapeutic drug monitoring in treating gram-positive infections.

by Megan Goodwin, PharmD, and Elizabeth Dodds Ashley, PharmD, BCPSSpecial to Infectious Disease News

Vancomycin, the only available glycopeptide antibiotic in the United States, continues to be a mainstay of therapy for gram-positive infections, especially methicillin-resistant Staphylococcus aureus (MRSA). With the incidence of MRSA exceeding 50% at many institutions, vancomycin is frequently used as part of empiric regimens as well as for treatment of documented infections.
Optimizing therapy with vancomycin is a challenge for clinicians due to several factors, including interpatient variability in pharmacokinetics. Therefore, serum concentration monitoring is often performed to ensure efficacy while preventing toxicity. One large problem, however, remains for vancomycin: the lack of standardized targets for serum concentration monitoring.

It has been historically believed that both the nephrotoxicities and ototoxicities associated with vancomycin occur as a result of elevated serum concentrations. Evidence, however, confirming causality of this theory is lacking. Most vancomycin-induced toxicity initially described was a result of older, impure formulations. The new, cleaner preparations are associated with a much lower incidence of these reactions. It is known that concomitant medications as well as underlying disease states have been and remain important risk factors for these adverse events. Still, it is generally believed that serum concentrations between 80 and 100 µg/mL may be linked to vancomycin toxicity.

Determining the appropriate target for efficacy is an even more challenging decision. Owing to the time-dependent killing properties of vancomycin, serum trough concentrations are the kinetic parameter most closely related with efficacy. Historically, a trough concentration in the range of 5 to 10 µg/mL was desired. This would easily achieve the goal concentration at two to four times the minimum inhibitory concentration (MIC) for commonly encountered organisms.
More recently, however, this target is being re-evaluated due to increasing vancomycin MICs and the growing number of vancomycin therapeutic fail ures. Some investigators have shown that MICs for Staphylococcus sp. to vancomycin have not been increasing in recent years.

Rather, perhaps “underdosing” of vancomycin is not new and has been associated with failures for decades. Independent of the reason, many clinicians are now targeting higher troughs for vancomycin (from 15 to 20 µg/mL), especially when treating more deep-seated infections (ie, meningitis, endocarditis, osteomyelitis), in which vancomycin penetration may also be an issue.

In 2005, the publication of two new sets of treatment guidelines gave clinicians published target vancomycin monitoring parameters for the first time. These recommendations are based on expert opinion, however, and remain somewhat controversial.

Pneumonia guidelines

The recent pneumonia guidelines, a joint publication from the American Thoracic Society and the Infectious Diseases Society of America (IDSA), advocate targeting higher vancomycin trough concentrations. Vancomycin is a large molecule, and we have known for sometime that penetration into the lung and other infection sites may be difficult. Therefore, increasing the target trough serum concentrations may result in higher pulmonary drug concentrations.

The recommended target vancomycin trough in these guidelines is 15 to 20 µg/mL. However, there are no specific data to say that troughs more than 15 µg/mL are associated with improved outcomes over trough levels more than 5 or 10 µg/mL. Two recent studies that compared linezolid (Zyvox, Pfizer) with vancomycin for nosocomial pneumonia were not able to find a difference between the two medications regarding treatment outcomes. However, a post hoc analysis of the combined results of the two trials showed that in patients with confirmed MRSA pneumonia, linezolid was associated with better survival and clinical cure rates. When these two studies are analyzed, one has to consider vancomycin dosing and monitoring. It appears that most patients received 1 g of vancomycin every 12 hours (a standard, nonpatient-specific dose), and plasma concentrations were not documented nor specifically targeted. For this reason, many believe that the only reason linezolid appears superior in this retrospective analysis is that vancomycin was not appropriately dosed in each patient. Hence, the recommendation in the new guidelines is higher than more traditional regimens. We hope future studies will be designed to compare clinical outcomes in patients treated with “properly dosed” vancomycin and other antimicrobials with anti-MRSA activity.

Endocarditis guidelines

Similarly, the American Heart Association in conjunction with the IDSA revised treatment recommendations for endocarditis in June 2005. The recently published endocarditis guidelines also recommend specific target concentrations for vancomycin.

Because many clinicians consider the vegetations involved in endocarditis to be relatively difficult to penetrate, the traditional target troughs were 15 to 20 µg/mL for this infection. The recent guidelines, however, recommend a lower trough concentration of 10 to 15 µg/mL. As with the pneumonia guidelines, these targets reflect the opinion of the expert panel in the absence of data to document the ideal target. As endocarditis typically presents with positive blood cultures and the location of the infection is actually inside the vascular system, the target trough of 10 to 15 µg/mL is likely reasonable. Endocarditis is also treated for a relatively long time depending on the cause and type of infection. Therefore, IV antibiotics, including vancomycin, may be continued for two to six weeks. In this situation, the targeting of vancomycin troughs of 10 to 15 µg/mL may help reduce the incidence of vancomycin toxicity.

The inclusion of peak concentration monitoring in these guidelines is intriguing. The expert panel recommended a target peak concentration of 30 to 45 µg/mL. Most clinicians rely solely on trough concentration monitoring given the predictable intrapatient kinetics of this agent and the lack of strong association for efficacy or toxicity with peak concentrations. There are specific instances in which measurement of vancomycin peak concentrations has historically been considered clinically important. These include infections located in sites that are difficult to penetrate and include central nervous system (CNS) infections, bone and joint infections and pneumonia. However, the clinical relevance or correlation of improved outcomes and specific peak concentrations has not been proven.

Therapy for resistant gram-positive infections remains challenging. Treatment strategies for these infections are evolving given the availability of new drugs and an increasing understanding of the appropriate administration for older agents. One such example is vancomycin, in which treatment regimens remain suboptimal and ill defined despite more than 50 years of use. These two recent publications are the first to document targets for vancomycin therapeutic drug monitoring. Hopefully, this will aid clinicians in maximizing efficacy of vancomycin therapy. Future studies will document the appropriateness of these recommendations and the role of vancomycin therapeutic drug monitoring in treating these infections.

For more information:

American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005;171:388-416.

Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anethesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation. 2005;111:3167-3184.

Elizabeth Dodds Ashley, PharmD, is a clinical pharmacist in Infectious Disease, and Megan Goodwin, PharmD, is a pharmacy practice resident, at Duke University in Durham, N.C.

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